Pyramidal neurons receive tens of thousands of excitatory an inhibitory synaptic inputs onto their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. We recently made the surprising finding that there is a very high density of transient, A-type K/+ channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent action potential in the dendrites, limit the back- propagation of action potential into the dendrites, and reduce the amplitudes of excitatory synaptic events. The channels thus exert a powerful control over dendritic signal propagation and neuronal excitability. In preliminary studies we have found that the activity of these channels is decreased by at least two prominent 2nd messenger, PKA and PKC. We also have evidence for the involvement of MAPK. The overall objective of this project is to understand the neuromodulation of this channel by neurotransmitters and 2nd messengers and to investigate the functional consequences of this modulation for the behavior of CA1 neurons. The specific aims are: 1) to test the hypothesis that dendritic, A-type K/+ channels are modulated by specific neurotransmitters and 2nd messenger systems; 2) to test the hypothesis that modulation of dendritic, A-type K/+ channels alters signal propagation in CA1 neurons; 3) to test the hypothesis that changes in dendritic, A-type K/+ channels enhance the induction and/or expression of synaptic plasticity; and 4) to test the hypothesis that dendritic, A-type K/+ channels are composed of the rat Kv4.2 alpha subunit. The proposed experiments will utilize rat hippocampal slices, dendritic patch-clamp recordings, and fluorescence imaging. The results of these experiments will provide basic information important for studies of temporal lobe epilepsy, Alzheimer's disease, schizophrenia, and depression.